Joint injuries such as ACL ruptures or meniscal tears typically occur in a young athletic population. Physicians acknowledge that even such relatively minor joint traumas ultimately progress to osteoarthritis in a majority of patients. Despite this, current clinical care does nothing at the time of injury to prevent the future onset of post-traumatic osteoarthritis (PTOA). Our global hypothesis is that PTOA begins at the cellular level just after joint injury occurs. The optimal time frame for effective therapeutic intervention is immediately after the injury, and the optimal therapeutic target will reduce the acute cellular response to the injury. We have developed a novel whole-joint injury model to initiate PTOA in mice. A single non-invasive mechanical load applied to the knee induces ACL rupture. Comparable to human ACL injuries, we observe an acute inflammatory response and joint swelling that resolves in a few days, extensive remodeling of subchondral bone, meniscus and cartilage, and OA (within 12 weeks in our model). The non-surgical nature of our injury model uniquely allows us to focus on the natural early events of joint injury that initiate the subsequen progression of OA. Joint trauma almost immediately triggers an acute cellular response. The acute response phase is characterized by the transcriptional activation of primary response genes and the release of inflammatory cytokines from joint tissues, which stimulates production of degradative enzymes involved with OA. Very recent evidence demonstrates that primary response genes are regulated at the transcription elongation step, with the rate-limiting step being the recruitment of cyclin-dependent kinase-9 (cdk9) to the transcription complex by NF?B. Thus, cdk9 kinase activity represents a new molecular target to inhibit the acute inflammatory response after joint injury. Specific cdk9 kinase inhibitors are readily available, an are currently in phase II clinical trials as anti-cancer drugs. Preliminary data support our hypothesis. We demonstrate that: 1) the acute cellular response in primary human chondrocytes is almost completely abolished by ckd9 inhibitor, with >90% repression of 37 different IL-1? induced genes, 2) these cell-based results were reproducible in cultured human osteochondral explants, in which cdk9 inhibitor also inhibits GAG release and decreases apoptosis; and 3) the treatment window to inhibit the acute cellular response is at least 3 hours in vitro. Our research strategy is to determine the time course of cdk9-dependent gene transcription immediately following joint injury, and then to assess the ability of cdk9 inhibitors to alter OA progression. Successful completion of this study will define a new class of PTOA prevention drugs based on inhibition of primary response inflammatory gene transcription. It will establish an early treatment window for joint injuries to prevent or delay the onset of PTOA. Translation to human clinical trials will follow.